أسئلة الخامسة GIT الدلتا

Definition & Location of Peptic Ulcer

• Defects in gastric or duodenal mucosa extend through the muscularis mucosa.
• Lower esophagus, distal duodenum, jejunum (in Zollinger Ellison syndrome), or ileum (in presence of Meckel's diverticulum) can be involved.
• Lesions ≥ 5mm are ulcers.
• Lesions < 5mm are erosions.
• Duodenum: First portion, anterior wall.
• Stomach: Usually antrum, lesser curvature (common), anterior and posterior wall, greater curvature (less common).
• Margins of a gastroenterostomy (stomal ulcer).
• In the duodenum, stomach or jejunum of patients with Zollinger-Ellison syndrome.
• Within or adjacent to a Meckel's diverticulum.

Etiology of Peptic Ulcer

• Helicobacter pylori is the most common cause.
• NSAID-associated PUD is the second most common cause.
• Corticosteroids, bisphosphonates, potassium chloride, and fluorouracil are medications that can cause PUD.
• Smoking plays a role in duodenal ulcers
• Alcohol can irritate the gastric mucosa and induce acidity.
• Zollinger-Ellison syndrome is a rare cause.
• Malignancy (gastric cancer, lymphomas) is a rare cause.
• Stress (acute illness, burns, head injury) is a rare cause.
• Viral infection is a rare cause.
• Vascular insufficiency is a rare cause.
• Radiation therapy & chemotherapy are rare causes.
• Crohn's disease is a rare cause.

Helicobacter Pylori-Associated PUD

• Gram-negative bacillus lives in the mucous layer overlying gastric epithelium, leading to inflammation.
• Can also be found within epithelial cells and attached to mucous cells.
• More prevalent among those with lower socioeconomic status and commonly acquired during childhood; about 50% of the world populations are infected.
• Transmitted orally (via saliva or vomit), fecally, or through waterborne routes due to fecal contamination.
• Iatrogenic infection can occur through inadequately sterilized endoscopes and nasogastric tubes.
• Mother-to-fetus transmission does not occur.
• Lives only in the gastric mucosa.
• Produces large amounts of urease enzyme that cleaves endogenous urea, producing an ammonia cloud that protects it from gastric acid.
• Infection causes gastric inflammation and inflammatory products provide nutrients for the bacteria.
• Gastric antrum is the predominant site of infection, but the gastric body can also be involved.
• Causes elevation of serum gastrin
• Elevated gastrin increases HCL secretion from the gastric body.
• Increased acid secretion and impaired duodenal secretion of bicarbonate damages the mucosa in the first part of the duodenum, leading to areas of gastric metaplasia that can be infected by H pylori.
• Duodenitis can then progress to ulcer.
• Virulence factors help with colonization and pathogenesis:
  • Urease enzyme and flagella are present in all strains.
  • Adhesins facilitate attachment of H-pylori to the mucosa.
  • Cytotoxin-associated antigen A (Cag A) is directly injected into the cytoplasm of mucosal cells, affecting cell shape, proliferation, and apoptosis.
  • H. pylori strains carrying Cag A have been associated with both duodenal ulcer and gastric cancer.
  • Vacuolating cytotoxin A (Vac A) is a pore-forming toxin which helps bacterial colonization.
  • Combined seropositivity for both Cag A and Vac A directly correlates with high morbidity.

Complications

• Chronic gastritis
• Peptic ulcer disease
• Non-ulcer dyspepsia
• Gastric malignancy (adenocarcinoma & Mucosal associated lymphoid tissue (MALT) lymphoma)
• Menterier disease: Rare disorder characterized by thickened mucosal folds in stomach body, diminished HCL secretion, increased mucous secretion, and protein-losing state with hypoalbuminemia.
  • In children, associated with CMV infection.
  • In adults, associated with H-pylori infection.
  • Overexpression of transforming growth factor (TGF)-alpha in gastric mucosa is the cause.
  • Males are affected more than females
  • Age older than 30 years.
  • Clinical presentation: Epigastric pain, fatigue, anorexia, weight loss, edema and vomiting, diarrhea, and gastrointestinal bleeding. Protein-losing enteropathy causes ascites, pleural effusion, and pericardial effusion.

NSAID-Associated PUD

• NSAID use is the second most common cause of PUD after H. pylori infection.
• Prostaglandin secretion normally protects the gastric mucosa.
• NSAIDs block prostaglandin synthesis by inhibiting the COX-1 enzyme, resulting in decreased gastric mucus and bicarbonate production and a decrease in mucosal blood flow.

Hypersecretory Environment

• Occurs in Zollinger Ellison syndrome.
• Can occur in Systemic mastocytosis.
• An antral G cell hyperplasia can cause a hypersecretory environment.

Severe Physiologic Stress

• Includes burns, central nervous system (CNS) trauma, surgery, and severe medical illness.
• Serious systemic illness, sepsis, hypotension, respiratory failure, and multiple traumatic injuries increase the risk for secondary (stress) ulceration.
• Cushing ulcers are associated with a brain tumor or injury.
• Curling ulcers are associated with extensive burns.

Zollinger Ellison Syndrome (ZES) (Gastrinoma)

• Gastrin-producing endocrine tumors of the pancreas (non-beta cells) or duodenum are the cause.
• Gastrin stimulates parietal cells, causing hypersecretion of HCL.
• Excessive HCL secretion leads to ulceration.
• Ulcers form in the duodenal bulb but may also be seen in the distal duodenum and jejunum, and multiple ulcers are commonly seen.
• Also causes diarrhea and malabsorption due to ulceration of the stomach and intestine, inactivation of pancreatic enzymes due to acidic pH (pancreatic enzymes work in alkaline pH), and precipitation of bile salts due to acidic pH.

Genetics

• More than 20% of patients have a family history of duodenal ulcers.
• Weak associations exist between duodenal ulcers and blood group O.
• Patients who do not secrete ABO antigens in their saliva and gastric juices are at higher risk.
• The reason for these apparent genetic associations is unclear.

Classification of Peptic Ulcer

• Stomach → gastric ulcer.
• Duodenum → duodenal ulcer.
• Esophagus → Esophageal ulcer.
• Meckel's Diverticulum → Meckel's Diverticulum ulcer.
• Type I: Ulcer along the lesser curve of stomach.
• Type II: Two ulcers present - one gastric, one duodenal/prepyloric.
• Type III: Prepyloric ulcer.
• Type IV: Proximal gastroesophageal ulcer.
• Type V: Anywhere (associated with chronic NSAID use).

Pathophysiology of Peptic Ulcer

• Peptic ulcers occur when the balance between aggressive factors and defensive mechanisms is disrupted.
• Aggressive factors: H pylori infection, NSAIDs, alcohol, bile salts, HCL, and pepsin.
• Defensive mechanisms: Tight intercellular junctions, mucus secretion, bicarbonate secretion, mucosal blood flow, cellular restitution, and epithelial renewal.
• Alteration of the mucosal defense by allowing the back diffusion of H ions leads to epithelial cell injury.

Histopathology of Peptic Ulcer

• Duodenal ulcers are four times more common than gastric ulcers.
• Duodenal ulcers are more common in men than women.
• Ulcer extends beyond the muscularis mucosa.
• Gastric ulcers are most commonly located on the lesser curvature.
• Duodenal ulcers are most common at the duodenal bulb (first part).
• The ulcer is round to oval with a smooth base.
• Acute ulcers have regular borders, while chronic ulcers have elevated borders with inflammation.

Clinical Picture of Peptic Ulcer

• Epigastric abdominal pain is the most common symptom, characterized by a gnawing or burning sensation after meals. Shortly after meals with gastric ulcer resulting in weight loss. Food relieves the pain of duodenal ulcers resulting in weight gain.
• Duodenal ulcer pain often awakens the patient at night and follows a daily pattern Pain with radiation to the back suggests a posterior penetrating gastric ulcer complicated by pancreatitis.
• Other common symptoms include bloating, abdominal fullness, nausea and vomiting, and weight loss (GU)/weight gain (DU).

Alarm Symptoms & Signs

• Iron deficiency anemia
• Unintentional weight loss
• Progressive dysphagia and odynophagia
• Overt gastrointestinal bleeding (Hematemesis and/or Melena)
• Recurrent vomiting
• Family history of upper gastrointestinal malignancy.
• Patients with alarm symptoms should be investigated for complications of PUD, predominantly bleeding, perforation, or cancer.

Physical Examination

• May reveal epigastric abdominal tenderness and signs of anemia.
• Succussion splash may result from partial or complete gastric outlet obstruction.

Differences Between Gastric Ulcer and Duodenal Ulcer

Complications of Peptic Ulcer

• First manifestation of people has a 15% chance of getting affected by this complication
• Can manifest as tarry stools or coffee-ground emesis
• Most common complication is hematemesis and/or melena
• Endoscopy is the standard of care for diagnosis and treatment.
• Perforation: Sudden severe abdominal pain, which can leads to peritonitis from leaked abdominal contents
  • Intense abdominal pain.
  • Ulcer may penetrate nearby organs like the liver or pancreas.
  • Serum amylase, lipase, and hepatic transaminases may be elevated.
• Gastric outlet obstruction: Present in 1-2% of people affected
  • Patients will exhibit the following:
  • Pain will worsen with meals, and Vomiting of undigested food
  • Inflammation and edema: Usually resolves around the ulcer healing
  • Mechanical: Requires an endoscopic balloon dilation (surgery) procedure for recovery
• Gastric Malignancy: Characterized by Adenocarcinoma and Mucosal-associated Lymphoid Tissue (MALT) lymphoma

Differential Diagnosis of Peptic Ulcer

• Gastritis: Inflammatory process of gastric mucosa presenting with upper abdominal pain and nausea, has a very similar clinical presentation to peptic ulcers
• GERD: Patients usually describe burning sensation in the epigastrium, with excessive salivation and intermittent regurgitation
• Gastric Cancer: Characterized with abdominal pain, patient will usually describe the symptoms like weight loss, melena, and recurrent vomiting
• Pancreatitis; Characterized with severe epigastric pain, can be managed in the supine position
• Biliary Colic: Intermittent, severe deep pain in the right upper quadrant (RUQ), precipitated with fatty meals
• Cholecystitis: Right upper quadrant/epigastric pain that lasts for hours. It’s exacerbated with fatty foods
• Myocardial infarction: patients show these symptoms, may be diagnosed with nausea and vomiting
• Mesenteric Ischemia: Chronic type can be presented with post-prandial epigastric pain; mainly affects older people
• Mesenteric Vasculitis: Can show unexplained abdominal pain, or lower gastrointestinal bleeding

Investigations of Peptic Ulcer

• Esophago-gastro-duodenoscopy (EGD):
  • Gold standard and most accurate diagnostic test. Sensitivity and specificity up to 90% in diagnosing GU and DU.
  • Gastric ulcers should be biopsied to exclude malignancy
  • Indications: Patients over 50 years of age with new onset of dyspeptic symptoms or for anyone with alarm symptoms irrespective of age.
• Barium swallow: It is indicated when EGD is contraindicated.
• Complete blood work, liver function, and levels of amylase and lipase.
• Serum gastrin: Patients with ZES usually have fasting serum gastrin levels of more than 200 pg/mL.
• CT of the abdomen with contrast: Used for diagnosis of complications as perforation, gastric malignancy, and gastric outlet obstruction.
• Helicobacter pylori testing: Current diagnostic methods include invasive and non-invasive tests.
  • Recommended to Stop PPIs at least one week before diagnosing H. pylori infection by UBT, stool antigen or endoscopic testing.
  • Perform these tests at least one month after management with antibiotics or Bismuth compounds to avoid false negative results.

A- NON-INVASIVE TESTS

• Antibodies (immunoglobulin G [IgG]) to H pylori can be measured in serum.
  • Advantages : Non-invasive, relatively cheap
  • Disadvantages: Can not differentiate past from current infection, miss one of every five cases
  • Usefulness: Initial diagnosis, not for follow up after therapy
• C13 Urea Breath Test
  • Advantages: no radio-activity, rapid, allows distinction between current and past infection, accurate in the presence of upper GIT bleeding
  • Disadvantages: complex equipment, expensive, reduced sensitivity with acid suppressants or antibiotics.
  • Usefulness: Initial diagnosis and follow up after therapy
• C14 Urea Breath Test
  • Acts as C13 but is slightly radioactive
  • Contraindicated in pregnant females and children

B - INVASIVE TESTS (ENDOSCOPIC)

• The most preferred Endoscopic diagnostic test.
• Looking for H pylori in gastric mucosal biopsy specimens is detected by testing for the H pylori urease.
• One or more Antral biopsy specimens are placed in the rapid urease test kit.
  • If H pylori is present, bacterial urease converts urea to ammonia, which changes the pH, resulting in a color change (Red).
  • Advantages: rapid , inexpensive
  • Disadvantages: reduced sensitivity in those on acid suppressants or with recent or active upper GIT bleeding
  • Usefulness: Initial diagnosis.
• Histology
  • Advantages : allows also assessment of the mucosa for atrophy, intestinal metaplasia or cancer
  • Disadvantages: invasive, costly, reduced sensitivity in those on acid suppressants.
  • Usefulness: Initial diagnosis.
• Culture and Sensitivity
  • Advantages: specificity 100%
  • Disadvantages: invasive, costly, not routinely available
  • Usefulness: Antimicrobial sensitivity study & strain typing.

Treatment of Peptic Ulcer

Antisecretory Drugs

• Prodrugs that, when activated by acid, bind to and inhibit the parietal cell H/K - ATPase.
• Because they require acid for activation, they are most effectively taken 30-60 minutes before a meal, except Dex-lansoprazole.

PPIs

• Indications include Esophagitis, Non-erosive reflux disease Peptic ulcer disease, Prevention of NDSAID induced ulcers Zollinger-Ellison Syndrome
• Part of the triple therapy regimen for Helicobacter pylori infections

H2-Receptor Antagonists (H2RA)

• Inhibit acid secretion by blocking the binding of histamine to its receptor on the parietal cell and inhibit both basal and food-induced acid secretion.
• Include cimetidine, famotidine, nizatidine, and ranitidine.
• H2RA doses should be adjusted in patients with renal insufficiency.
• H2RA are most effective when administered between dinner and bedtime.

Prostaglandin Analog

• Misoprostol inhibits HCL secretion.
• Is the only drug that has been approved for prophylaxis of NSAID-induced peptic ulcers.
• Due to its mechanism of action Misoprostol may cause diarrhea or spontaneous abortion.
• PPIs have largely replaced H2 receptor blockers due to their superior healing and efficacy.
• PPIs block acid production in the stomach, providing relief of symptoms and promote ulcer healing.

H. Pylori-Induced PUD

• H. pylori-induced PUD is managed via a triple regimen comprised of two antibiotics and a proton pump inhibitor.
• Pantoprazole, clarithromycin, and metronidazole, or amoxicillin are used for 7 to 14 days.
• Antibiotics and PPIs work synergistically to eradicate H. pylori.
• The antibiotics selected should take into consideration the presence of antibiotic resistance in the environment.
• Quadruple therapy with bismuth and different antibiotics is used if first-line therapy fails

NSAIDs Induced PUD

• Can be managed by stopping the use of NSAIDs or switching to a lower dose or selective COX 2 inhibitor.
• Corticosteroids, bisphosphonates, and anticoagulants should also be discontinued if possible.
• Prostaglandin analog (Misoprostol) are sometimes used as prophylaxis and treatment for NSAID-induced peptic ulcers.

Endoscopic Treatment of Peptic Ulcer

• Endoscopic treatment according to Forrest:
  • Endoscopic treatment is mandatory for ulcers with active bleeding or with a non-bleeding visible vessel.
  • Endoscopic treatment is generally not recommended for ulcers with hematin on the ulcer base or a clean ulcer base.
• Ulcers with an adherent clot need endoscopic treatment, but treatment is generally recommended when the clot is resistant to vigorous water irrigation.
• FORREST IA - spurting hemorrhage
  • FORREST IB oozing hemorrhage
  • FORREST IIA - visible vessel
  • FORREST IIB - Adherent clot
  • FORREST IIC - Hematin on ulcer base
  • FORREST III - Clean ulcer base

Methods of Endoscopic Treatment of PUB

• Consists of epinephrine, sclerosants (absolute ethanol, polidocanol), and tissue adhesives (thrombin/fibrin glues).
• Injection of epinephrine is the most widely used method for control of bleeding. Adding a second therapy such as thermal or mechanical is significantly more effective than epinephrine alone in reducing bleeding and surgery.
• Diluted epinephrine (1:10,000 or 1:20,000) is injected in 0.2 to 2 mL doses in all four quadrants of the bleeding ulcer.
• Contact methods consists of heater probe or bipolar electrocoagulation
• Non-contact methods consist of argon plasma coagulation (APC)
• The mechanical therapy (Clips) is more effective than epinephrine injection in reducing further bleeding and surgery but less effective than thermal therapy.

Additional Treatments

• Another salvage regimen that is not available in Egypt is combination of PPI twice daily, rifabutin 300 mg once daily and Amoxicillin 1gm twice daily, for 10 days.
• Recently, vonoprazan (20 mg) , a potassium competitive acid blocker (PCAB), is approved for the treatment of H. pylori infection in adults when used in combination with amoxicillin (dual therapy), or amoxicillin and clarithromycin (triple therapy).

Surgical treatment of PUB

• Peptic ulcer disease (PUD) is now medically managed in the majority of patients.
• The surgical treatment of PUD is now indicated in:
  • Free perforation
  • Refractory bleeding
  • Gastric outlet obstruction